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Trimethoprim-Sulfamethoxazole and Clozapine

To the Editor: Clozapine, an atypical antipsychotic drug, is associated with a .8 percent incidence of agranulocytosis when taken for more than 52 weeks (1). Other classes of drugs, including antithyroid drugs, nonsteroidal anti-inflammatory drugs, antibiotics, sulfonamides, cardiotonics, and anticonvulsants, have been associated with a higher risk of neutropenia and agranulocytosis (2). Trimethoprim-sulfamethoxazole, initially introduced for the treatment of urinary or respiratory tract infections, has been associated with neutropenia and thrombocytopenia. Thrombocytopenia is defined as a platelet count of less than 100 x 10³/µL (3,4).

We present a case of neutropenia and thrombocytopenia that may have been related to a combination of clozapine and trimethoprim-sulfamethoxazole.

Ms. A was a 47-year old woman with a 22-year history of schizoaffective disorder, bipolar type, and panic disorder. She responded well to 375 mg a day of clozapine over five and a half years. Clozapine was well tolerated, and Ms. A's white blood cell count ranged from a low of 6.3 x 10³/µL to a high of 13.1 x 10³/µL. During this period she experienced several episodes of bronchitis and was successfully treated with cephalexin and cephalothin. She had been treated at least twice with trimethoprim-sulfamethoxazole and experienced only mild stomach upset.

In August 1998, after she had been taking clozapine for five years, Ms. A was treated with double-strength trimethoprim-sulfamethoxazole for bronchitis. Four days after she started taking the antibiotic, she complained to her internist about confusion and exhaustion. A blood sample was drawn late in the day, and trimethoprim-sulfamethoxazole was immediately discontinued. The following day, Ms. A visited the internist complaining of confusion, paranoia, disorganization, and exhaustion. Analysis of the previous day's blood sample showed a white blood cell count of 2.3 x 10³/µL, with 65.8 percent polymorphonuclear neutrophils, 30.3 percent lymphocytes, 3.9 percent monocytes, an absolute neutrophil count of 1,513.4/mm³, a platelet count of 102 x 10³/µL, and normal red blood cell indexes.

Ms. A was transported to a general hospital for further evaluation. Repeat tests showed a white blood cell count of 4.8 x 10³/µL and a platelet count of 66 x 10³/µL. The white cell differential included 43 percent polymorphonuclear neutrophils, 9 percent bands, 30 percent lymphocytes, 3 percent atypical lymphocytes, 13 percent monocytes, 1 percent myelocytes, 1 percent metacytes, and an absolute neutrophil count of 2,496/ mm³. Other medical causes of neutropenia and thrombocytopenia were ruled out.

Ms. A's blood cell counts returned to baseline within five days. Two weeks after trimethoprim-sulfamethoxazole was discontinued, a follow-up analysis showed a white blood cell count of 6.6 x 10³/µL, a platelet count of 232 x 10³/µL, an absolute neutrophil count of 2,706/mm³, and a normal differential.

Ms. A's clinical picture was consistent with trimethoprim-sulfamethoxazole-induced neutropenia—an absolute neutrophil count below 1,800/mm³—and thrombocytopenia. Both disorders resolved after trimethoprim-sulfamethoxazole was discontinued.

Clozapine may have enhanced the bone marrow-suppressive effect of trimethoprim-sulfamethoxazole, leading to the development of neutropenia and thrombocytopenia in a patient who previously tolerated both drugs without incident. Although most physicians are aware of the risks of prescribing a combination of carbamazepine and clozapine, few pay close attention to the risks of prescribing antibiotics such as trimethoprim-sulfamethoxazole, which may have a greater relative risk of neutropenia than carbamazepine (2). Patients taking clozapine should be closely monitored when trimethoprim-sulfamethoxazole is prescribed.

Footnotes

The authors are affiliated with the psychotic disorders program at Massachusetts General Hospital and the Erich Lindemann Mental Health Center in Boston.

References

1. Alvir JM, Lieberman JA, Safferman AZ, et al: Clozapine-induced agranulocytosis: incidence and risk factors in the United States. New England Journal of Medicine 329:162-167, 1993[Abstract/Free Full Text]
2. Young N: Agranulocytosis. JAMA 271:935-938, 1994[Abstract/Free Full Text]
3. Keisu M, Wiholm B, Palmblad J: Trimethoprim-sulphamethoxazole-associated blood dyscrasias: ten years' experience of the Swedish spontaneous reporting system. Journal of Internal Medicine 228:353-360, 1990[Medline]
4. Dickson H: Trimethoprim-sulphamethoxazole and thrombocytopenia. Medical Journal of Australia 2:5-7, 1978

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